Patent EA-003677-B1 (EA)
Title: Aliphatic amino carboxylic and amino phosphonic acids, amino nitriles and amino tetrazoles as cellular rescue agents
Inventor: PATERSON ALICK I
IPC: A61P13/12
Filed: 1999-03-25
Abstract: 1. A compound of the Formula I wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, wherein R1 may be optionally substituted with one or more substituents selected from hydroxy, aldehyde, oxo, lower acyloxy, halogen, thio, sulfoxide and sulfone, R2 = H, CH3 or CH2CH3, R3 = H or CH3, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, as a substantially pure enantiomer in the R or S configuration at a carbon atom to which R1, R2 and R3 substituents are attached or a pharmaceutically acceptable salt thereof. 2. A compound of the Formula I according to claim 1 wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 wherein R1 and R2 substituents have different meanings, R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, or a pharmaceutically acceptable salt thereof. 3. A compound of the Formula I according to claim 1 wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 wherein R1 and R2 substituents have different meanings, R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, or a pharmaceutically acceptable salt thereof. 3. A compound of the Formula I according to claim 1 wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 wherein R1 and R2 substituents have different meanings, R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, as a substantially pure enantiomer in the R-configuration, or a pharmaceutically acceptable salt thereof. 4. A compound of the Formula I according to claim 1 wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 wherein R1 and R2 substituents have different meanings, R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, as a substantially pure enantiomer in the S-configuration, or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 3, wherein said compound of formula 1 is selected from the group consisting of: (R)-3-(2-Heptylamino)propionic acid; (R)-3-(2-Heptylmethylamino)propionic acid; Methyl (R)-3-(2-heptylamino)propionate; Methyl (R)-3-(2-heptytmethylamino)propionate; (R)-2-(2-Pentylamino)acetonitrile; (R)-2-(2-Pentylmethylamino)acetonitrile; (R)-3-(2-Heptylamino)propionitrile; (R)-3-(2-Heptylmethylamino)propionitrile; (R)-2-(2-Pentylamino)ethanephosphonic acid; (R)-2-(2-Pentylmethylamino)ethanephosphonic acid; and (R)-2-(2-Heptylamino)ethane-5-tetrazole. 6. A compound according to claim 4, wherein said compound of formula I is selected from the group consisting of: (S)-2-(2-Heptylamino)acetic acid; (S)-2-(2-Heptylmethylamino)acetic acid; Methyl (S)-2-(2-heptylamino)acetate; Methyl (S)-2-(2-heptylmethylamino)acetate; (S)-2-(2-Heptylamino)acetonitrile; (S)-2-(2-Heptylmethylamino)acetonitrile; (S)-2-(2-Heptylamino)ethanephosphonic acid; and (S)-2-(2-Heptylmethylamino)ethanephosphonic acid. 7. A compound selected from the group consisting of: 2-(1-Hexylmethylamino)acetic acid; 3-(2-Propylmethylamino)propionic acid; Methyl 2-(2-propylmethylamino)acetate; Methyl 2-(1-hexylmethylamino)acetate; Methyl 3-(1-hexylmethylamino)propionate; 2-(1-Hexylamino)acetonitrile; 2-(1-Hexylmethylamino)acetonitrile; 3-(3-Pentylamino)propionitrile; 3-(3-Pentylmethylamino)propionitrile; 2-(2-Propylamino)ethanephosphonic acid; and 2-(2-Propylmethylamino)ethanephosphonic acid. 8. A compound according to any one of claims 1 to 7 in the form of a hydrochloride salt. 9. A compound according to any one of claims 1 to 4 wherein m is an integer from 1 to 12. 10. A compound according to any one of claims 1 to 4 wherein m is an integer from 1 to 9. 11. A composition for the treatment or prevention of a disease in which cell death occurs by apoptosis, which composition comprises an effective amount of a compound having the formula I: wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, wherein R1 may be optionally substituted with one or more substituents selected from hydroxy, aldehyde, oxo, lower acyloxy, halogen, thio, sulfoxide and sulfone, R2 = H, CH3 or CH2CH3, R3 = H or CH3, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, as a substantially pure enantiomer in the R or S configuration at a carbon atom to which R1, R2 and R3 substituents are attached or a pharmaceutically acceptable salt thereof. 12. A composition according to claim 11, wherein: R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 wherein R1 and R2 substituents have different meanings, R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, or a pharmaceutically acceptable salt thereof, in admixture with a suitable diluent or carrier. 13. A composition according to claim 11, wherein said compound of formula I is selected front the group consisting of: (R)-3-(2-Heptylamino)propionic acid; (R)-3-(2-Heptylmethylamino)propionic acid; Methyl (R)-3-(2-heptylamino)propionate; Methyl (R)-3-(2-heptylmethylamino)propionate; (R)-2-(2-Pentylamino) acetonitrile; (R)-2-(2-Pentylmethylamino)acetonitrile; (R)-3-(2-Heptylamino)propionitrile; (R)-3-(2-Heptylmethylamino)propionitrile; (R)-2-(2-Pentylamino)ethanephosphonic acid; (R)-2-(2-Penlylmethylamino)ethanephosphonic acid; and (R)-2-(2-Heptylamino)ethane-5-tetrazole. 14. A composition according to claim 11, wherein said compound of formula I is selected from the group consisting of: (S)-2-(2-Heptylamino)acetic acid; (S)-2-(2-Heptylmethylamino)acetic acid; Methyl (S)-2-(2-heptylamino)acetate; Methyl (S)-2-(2-heptylmethylamino)acetate; (S)-2-(2-Heptylamino)acetonitrile; (S)-2-(2-Heptylmethylamino)acetonitrile; (S)-2-(2-Heptylamino)ethanephosphonic acid; and (S)-2-(2-Heptylmethylamino)ethanephosphonic acid. 15. A composition for the treatment or prevention of a disease in which cell death occurs by apoptosis, which composition comprises an effective amount of a compound selected from the group consisting of: 2-(1-Hexylmethylamino)acetic acid; 3-(2-Propylmethylamino)propionic acid; Methyl 2-(2-propylmethylamino)acetate; Methyl 2-(1-hexylmethylamino)acetate; Methyl 3-(1-hexylmethylamino)propionate; 2-(1-Hexylamino)acetonitrile; 2-(1-Hexylmethylamino)acetonitrile; 3-(3-Pentylamino)propionitrile; 3-(3-Pentylmethylamino)propionitrile; 2-(2-Propylamino)ethanephosphonic acid; and 2-(2-Propylmethylamino)ethanephosphonic acid in admixture with a suitable diluent or carrier. 16. A, composition according to any one of claims 11 to 15, wherein the compound of formula I is in the form of a hydrochloride salt. 17. A use of a compound of the formula I R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, wherein R1 may be optionally substituted with one or more substituents selected from hydroxy, aldehyde, oxo, lower acyloxy, halogen, thio, sulfoxide and sulfone, R2 = H, CH3 or CH2CH3, R3 = H or CH3, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, as a substantially pure enantiomer in the R or S configuration at a carbon atom to which R1, R2 and R3 substituents are attached or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease in which cell death occurs by apoptosis. 18. A use according to claim 17, wherein R1 is (CH2)mCH3 where m is 0 or an integer in the range from 1 to 16, R2 = CH3 R3 = H, R4 = H or CH3, R5 = lower alkyl having from 1 to 5 carbon atoms, n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR5), cyano (C [triple bond] N), phosphonic acid (PO3H2), phosphonate ester (PO3[R5]2) or 5-tetrazole, or a pharmaceutically acceptable salt thereof. 19. A use according to claim 17 or 18 wherein the compound of the formula I is a substantially pure enantiomer in the R configuration. 20. A use according to claim 17 or 18 wherein the compound of the Formula I is a substantially pure enantiomer in the S configuration. 21. A use according to claim 17 wherein said compound of Formula I is selected from the group consisting of: 2-(2-Propylamino)acetic acid; 2-(1-Hexylamino)acetic acid; (S)-2-(2-Heptylamino)acetic acid; 3-(2-Propylamino)propionic acid; 3-(1-Hexylamino)propionic acid; (R)-3-(2-Heptylamino)